Dietary grape polyphenol resveratrol increases mammary tumor growth and metastasis in immunocompromised mice

BMC Complementary and Alternative Medicine

Suranganie Dharmawardhane³  Luis A Cubano¹  Linette Castillo-Pichardo² 

[1] Department of Anatomy and Cell Biology, Universidad Central del Caribe School of Medicine, Bayamon, Puerto Rico;Department of Pathology and Laboratory Medicine, Universidad Central del Caribe School of Medicine, Bayamon, Puerto Rico;Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, Puerto Rico

关键词: Rac;    Grape polyphenols;    Metastasis;    Resveratrol;    Breast cancer;   

Others  :  1231170
DOI  :  10.1186/1472-6882-13-6

 received in 2012-07-20, accepted in 2013-01-02,  发布年份 2013

【 摘 要 】

Background

Resveratrol, a polyphenol from grapes and red wine has many health beneficial effects, including protection against cardiovascular and neurodegenerative diseases and cancer. However, our group and others have provided evidence for a dual cancer promoting or inhibitory role for resveratrol in breast cancer, dependent on estrogenic or antiestrogenic activities. Moreover, much of the inhibitory effects of resveratrol have been reported from studies with high non-physiological concentrations.

Methods

We investigated the effects of a range of concentrations (0.5, 5, 50 mg/kg body weight) of resveratrol on mammary tumor development post-initiation, using immunocompromised mice.

Results

Our findings suggest promotion of mammary tumor growth and metastasis by resveratrol at all concentrations tested in tumors derived from the low metastatic estrogen receptor (ER)α(-), ERβ(+) MDA-MB-231 and the highly metastatic ER(-) MDA-MB-435 cancer cell lines. Additionally, the activity of the migration/invasion regulator Rac, which we have previously shown to be regulated by resveratrol in vitro, was measured in tumors from resveratrol treated mice. Our results show a significant induction of tumoral Rac activity and a trend in increased expression of the Rac downstream effector PAK1 and other tumor promoting molecules following resveratrol treatment.

Conclusion

Taken together, our findings implicate low concentrations of resveratrol in potential promotion of breast cancer. Therefore, this study illuminates the importance of further delineating resveratrol’s concentration dependent effects, particularly in breast cancer, before it can be tested in the clinic or used as a dietary supplement for breast cancer patients.

【 授权许可】

   
2013 Castillo-Pichardo et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Gomez-Serranillos MP, Martin S, Ortega T, Palomino OM, Prodanov M, Vacas V, et al.: Study of red wine neuroprotection on astrocytes. Plant Foods Hum Nutr 2009, 64:238-243.
• [2]Xia EQ, Deng GF, Guo YJ, Li HB: Biological activities of polyphenols from grapes. Int J Mol Sci 2010, 11:622-646.
• [3]Ndiaye M, Kumar R, Ahmad N: Resveratrol in cancer management: where are we and where we go from here? Ann N Y Acad Sci 2011, 1215:144-149.
• [4]Shukla Y, Singh R: Resveratrol and cellular mechanisms of cancer prevention. Ann N Y Acad Sci 2011, 1215:1-8.
• [5]Fulda S, Debatin KM: Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect Prev 2006, 30:217-223.
• [6]Bhat KP, Lantvit D, Christov K, Mehta RG, Moon RC, Pezzuto JM: Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res JID - 2984705R 2001, 61:7456-7463.
• [7]Bowers JL, Tyulmenkov VV, Jernigan SC, Klinge CM: Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology 2000, 141:3657-3667.
• [8]Levenson AS, Gehm BD, Pearce ST, Horiguchi J, Simons LA, Ward JE III, et al.: Resveratrol acts as an estrogen receptor (ER) agonist in breast cancer cells stably transfected with ER alpha. Int J Cancer 2003, 104:587-596.
• [9]Filomeni G, Graziani I, Rotilio G, Ciriolo MR: Trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways. Genes Nutr 2007, 2:295-305.
• [10]Nguyen TH, Mustafa FB, Pervaiz S, Ng FS, Lim LH: ERK1/2 activation is required for resveratrol-induced apoptosis in MDA-MB-231 cells. Int J Oncol 2008, 33:81-92.
• [11]Alkhalaf M: Resveratrol-induced growth inhibition in MDA-MB-231 breast cancer cells is associated with mitogen-activated protein kinase signaling and protein translation. Eur J Cancer Prev 2007, 16:334-341.
• [12]De AF, Giordano F, Vivacqua A, Pellegrino M, Panno ML, Tramontano D, et al.: Resveratrol, through NF-Y/p53/Sin3/HDAC1 complex phosphorylation, inhibits estrogen receptor {alpha} gene expression via p38MAPK/CK2 signaling in human breast cancer cells. FASEB J 2011, 25:3695-707.
• [13]Araujo JR, Goncalves P, Martel F: Chemopreventive effect of dietary polyphenols in colorectal cancer cell lines. Nutr Res 2011, 31:77-87.
• [14]Szekeres T, Saiko P, Fritzer-Szekeres M, Djavan B, Jager W: Chemopreventive effects of resveratrol and resveratrol derivatives. Ann N Y Acad Sci 2011, 1215:89-95.
• [15]Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB: Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 2011, 1215:150-160.
• [16]Brownson DM, Azios NG, Fuqua BK, Dharmawardhane SF, Mabry TJ: Flavonoid effects relevant to cancer. J Nutr JID - 0404243 2002, 132:3482S-3489S.
• [17]Azios NG, Dharmawardhane SF: Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. Neoplasia 2005, 7:128-140.
• [18]Johnson JJ, Nihal M, Siddiqui IA, Scarlett CO, Bailey HH, Mukhtar H, et al.: Enhancing the bioavailability of resveratrol by combining it with piperine. Mol Nutr Food Res 2011, 55:1169-1176.
• [19]Santos AC, Veiga F, Ribeiro AJ: New delivery systems to improve the bioavailability of resveratrol. Expert Opin Drug Deliv 2011, 8:973-990.
• [20]Garvin S, Ollinger K, Dabrosin C: Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett 2006, 231:113-122.
• [21]Osmond GW, Augustine CK, Zipfel PA, Padussis J, Tyler DS: Enhancing melanoma treatment with resveratrol. J Surg Res 2012, 172:109-115.
• [22]Niles RM, Cook CP, Meadows GG, Fu YM, McLaughlin JL, Rankin GO: Resveratrol is rapidly metabolized in athymic (nu/nu) mice and does not inhibit human melanoma xenograft tumor growth. J Nutr 2006, 136:2542-2546.
• [23]Fukui M, Yamabe N, Zhu BT: Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur J Cancer 2010, 46:1882-1891.
• [24]Patel KR, Scott E, Brown VA, Gescher AJ, Steward WP, Brown K: Clinical trials of resveratrol. Ann N Y Acad Sci 2011, 1215:161-169.
• [25]Smoliga JM, Baur JA, Hausenblas HA: Resveratrol and health–a comprehensive review of human clinical trials. Mol Nutr Food Res 2011, 55:1129-1141.
• [26]Castillo-Pichardo L, Martinez-Montemayor MM, Martinez JE, Wall KM, Cubano LA, Dharmawardhane S: Inhibition of mammary tumor growth and metastases to bone and liver by dietary grape polyphenols. Clin Exp Metastasis 2009, 26:505-516.
• [27]Lacroix M: MDA-MB-435 cells are from melanoma, not from breast cancer. Cancer Chemother Pharmacol 2009, 63:567.
• [28]Sellappan S, Grijalva R, Zhou X, Yang W, Eli MB, Mills GB, et al.: Lineage infidelity of MDA-MB-435 cells: expression of melanocyte proteins in a breast cancer cell line. Cancer Res 2004, 64:3479-3485.
• [29]Chambers AF: MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res 2009, 69:5292-5293.
• [30]Yang M, Baranov E, Jiang P, Sun FX, Li XM, Li L, et al.: Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc Natl Acad Sci USA 2000, 97:1206-1211.
• [31]Hoffman RM, Yang M: Whole-body imaging with fluorescent proteins. Nat Protoc 2006, 1:1429-1438.
• [32]Hoffman RM: The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat Rev Cancer 2005, 5:796-806.
• [33]Carlson AL, Hoffmeyer MR, Wall KM, Baugher PJ, Richards-Kortum R, Dharmawardhane SF: In situ analysis of breast cancer progression in murine models using a macroscopic fluorescence imaging system. Lasers Surg Med 2006, 38:928-938.
• [34]Schlachterman A, Valle F, Wall KM, Azios NG, Castillo L, Morell L, et al.: Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model. Transl Oncol 2008, 1:19-27.
• [35]Martinez-Montemayor MM, Otero-Franqui E, Martinez J, De LM-P, Cubano LA, Dharmawardhane S: Individual and combined soy isoflavones exert differential effects on metastatic cancer progression. Clin Exp Metastasis 2010, 27:465-480.
• [36]Azios NG, Krishnamoorthy L, Harris M, Cubano LA, Cammer M, Dharmawardhane SF: Estrogen and resveratrol regulate Rac and Cdc42 signaling to the actin cytoskeleton of metastatic breast cancer cells. Neoplasia 2007, 9:147-158.
• [37]Le CC, Carlier MF: Regulation of actin assembly associated with protrusion and adhesion in cell migration. Physiol Rev 2008, 88:489-513.
• [38]Lee MH, Choi BY, Kundu JK, Shin YK, Na HK, Surh YJ: Resveratrol suppresses growth of human ovarian cancer cells in culture and in a murine xenograft model: eukaryotic elongation factor 1A2 as a potential target. Cancer Res 2009, 69:7449-7458.
• [39]Chen J, Dong XS, Guo XG: Inhibitory effect of resveratrol on the growth of human colon cancer ls174t cells and its subcutaneously transplanted tumor in nude mice and the mechanism of action. Zhonghua Zhong Liu Za Zhi 2009, 31:15-19.
• [40]Bishayee A, Dhir N: Resveratrol-mediated chemoprevention of diethylnitrosamine-initiated hepatocarcinogenesis: inhibition of cell proliferation and induction of apoptosis. Chem Biol Interact 2009, 179:131-144.
• [41]Perez-Vizcaino F, Duarte J, Santos-Buelga C: The flavonoid paradox: conjugation and deconjugation as key steps for the biological activity of flavonoids. J Sci Food Agric 2012, 92:1822-1825.
• [42]Laajala TD, Corander J, Saarinen NM, Makela K, Savolainen S, Suominen MI, et al.: Improved statistical modeling of tumor growth and treatment effect in preclinical animal studies with highly heterogeneous responses in vivo. Clin Cancer Res 2012, 18:4385-4396.
• [43]Mukherjee S, Dudley JI, Das DK: Dose-dependency of resveratrol in providing health benefits. Dose-Response 2010, 8:478-500.
• [44]Whitlock NC, Baek SJ: The anticancer effects of resveratrol: modulation of transcription factors. Nutr Cancer 2012, 64:493-502.
• [45]Pezzuto JM: The phenomenon of resveratrol: redefining the virtues of promiscuity. Ann N Y Acad Sci 2011, 1215:123-130.
• [46]Wang Y, Romigh T, He X, Orloff MS, Silverman RH, Heston WD, et al.: Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. Hum Mol Genet 2010, 19:4319-4329.
• [47]Chen HJ, Hsu LS, Shia YT, Lin MW, Lin CM: The beta-catenin/TCF complex as a novel target of resveratrol in the Wnt/beta-catenin signaling pathway. Biochem Pharmacol 2012, 84:1143-1153.
• [48]Chang CY, McDonnell DP: Molecular pathways: the metabolic regulator estrogen-related receptor alpha as a therapeutic target in cancer. Clin Cancer Res 2012, 18:6089-6095.
• [49]Ariazi EA, Jordan VC: Estrogen-related receptors as emerging targets in cancer and metabolic disorders. Curr Top Med Chem 2006, 6:203-215.